The overall goal is to use murine experimental autoimmune thyroiditis (EAT) as a model to probe the recognitory, pathogenic, and regulatory mechanisms, both promoting and inhibiting thyroid damage in Hashimoto's thyroiditis (HT), the hypothyroid syndrome. A major thrust in this renewal application is the emphasis on the use of specific HLA single and double class II transgenic mice and major human thyroid antigens and a novel H2E transgenic model because of new findings in the previous years. These include: 1) Identification of HLA-DRB1 and DQ transgenes responsible for susceptibility and resistance to EAT induced with either human thyroglobulin (hTg) or mouse (m) Tg, thereby demonstrating polymorphism in EAT susceptibility and resistance. 2) In the presence of resistant class II alleles, EAT development is down-modulated; an example is DQ8 transgene moderating DR3-mediated susceptibility. 3) The unusual H2E model is permissive only for hTg, but not mTg, induction, unlike conventional, susceptible strains. 4) For both HLA and H2E transgenic models, specific Tg epitopes derived from computer modeling have proven thyroiditogenic, revealing hTg-unique epitopes. The recent success in genetic immunization with DNA has provided renewed impetus to extend our models to two other major thyroid antigens. We propose to: 1. Characterize the novel H2AE+ transgenic model with distinct permissiveness for hTg. 2. Examine the response of HLA-DR3 transgenic mice to Tg and thyroiditogenic epitopes under the influence of protective class II alleles and environmental factors. 3. Determine if HLA association with Tg correlates with other major thyroid antigens-genetic immunization with thyroid peroxidase (hTPO) and thyroid-stimulating hormone receptor (hTSHR). 4. Characterize the mechanisms of T cell regulation in mTg-induced resistance.